Studies of HPV vaccine efficacy usually record infections with vaccine targeted and nontargeted strains. Contrary to blinded randomized controlled trials, confounding bias can be a threat and risk compensation may occur in observational studies. Etievant et al. (Biometrics, 2023) proposed to use cervical infections with nontargeted HPV strains to reduce or remove confounding bias of estimates of vaccine efficacy on targeted strains. However, they assumed that vaccinated women could not change their behavior after vaccination. We consider a more plausible setting where unmeasured sexual behavior acts as both a confounder and a mediator, and investigate if the quantity estimated in practice with their method has a clear causal meaning. We demonstrate that using nontargeted HPV infections can remove both confounding bias and the portion of the vaccine effect on the targeted HPV strains that is mediated through the change of behavior. In that case, the estimated quantity has a clear causal interpretation as it represents the direct immunological effect of the vaccine. However, it could be considered misleading from a public health perspective, as in the presence of risk compensation it would suggest higher protection than what women effectively experience. An unblinded randomized controlled trial would allow estimation of the total causal effect of the vaccine, and infections with nontargeted HPV strains could then be used to isolate the indirect behavioral effect of the vaccine.

翻译：HPV疫苗效力研究通常同时记录疫苗靶向和非靶向株系的感染情况。与盲法随机对照试验不同，观察性研究中可能存在混杂偏倚风险和行为风险补偿效应。Etievant等人（Biometrics, 2023）提出利用宫颈非靶向HPV株系感染来减少或消除靶向株系疫苗效力估计中的混杂偏倚，但该研究假设接种疫苗的女性不会在接种后改变行为。我们考虑更符合实际情况的设定，即未测量的性行为既作为混杂因素又作为中介变量，探究其方法实际估计量是否具有明确的因果含义。研究表明，利用非靶向HPV感染可以同时消除混杂偏倚和通过行为改变介导的疫苗对靶向HPV株系效应部分。在此情况下，估计量具有清晰的因果解释，代表疫苗的直接免疫学效应。然而从公共卫生视角看，该估计量可能具有误导性——在存在风险补偿现象时，其暗示的保护效力将高于女性实际获得的保护水平。非盲法随机对照试验可评估疫苗的总因果效应，而利用非靶向HPV株系感染则可分离出疫苗的间接行为效应。